7. Compounds according to claim 1 in which Het2 particularly
preferably denotes pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl,
each of which is unsubstituted or mono- or di substituted by Hal, OH, OA,
A and/or ═O.

and pharmaceutically usable salts and stereoisomers thereof, including
mixtures thereof in all ratios.

10. Process for the preparation of compounds of the formula I and
pharmaceutically usable salts, and stereoisomers thereof, characterised
in that a compound of the formula II ##STR00148## in which R2,
R3, R4, R5 and p, have the meanings indicated in claim 1,
is reacted with a compound of the formula III or formula IV ##STR00149##
in which R1, m, D, Z, X and Y have the meanings indicated in claim
1 and L is a halogen, tosylate, mesylate or triflate, and/or a base or
acid of the formula I is converted into one of its salts.

11. Medicaments comprising at least one compound of the formula I
according to claim 1 and/or pharmaceutically usable salts and
stereoisomers thereof, including mixtures thereof in all ratios, and
optionally excipients and/or adjuvants.

12. A method for the treatment of diseases in which the inhibition,
regulation and/or modulation of phosphodiesterase or lysophospholipase
autotaxin plays a role, comprising administering to a patient an
effective amount of a compound according to claim 1.

13. A method for the treatment and prophylaxis of cancer diseases,
comprising administering to a patient an effective amount of a compound
according to claim 1.

14. A method according to claim 13, where the cancer diseases are
associated with a tumour from the group of tumours of the squamous
epithelium, of the bladder, of the stomach, of the kidneys, of head and
neck, of the oesophagus, of the cervix, of the thyroid, of the intestine,
of the liver, of the brain, of the prostate, of the urogenital tract, of
the lymphatic system, of the stomach, of the larynx and/or of the lung.

15. A method according to claim 14, where the tumour originates from the
group monocytic leukaemia, lung adenocarcinoma, small-cell lung
carcinomas, pancreatic cancer, ovarian carcinoma, glioblastomas and
breast carcinoma and colon carcinoma.

16. A method according to claim 15, where the disease to be treated is a
tumour of the blood and immune system.

17. A method according to claim 16, where the tumour originates from the
group of acute myeloid leukaemia, chronic myeloid leukaemia, acute
lymphatic leukaemia and/or chronic lymphatic leukaemia.

Description:

BACKGROUND OF THE INVENTION

[0001] The invention was based on the object of finding novel compounds
having valuable properties, in particular those which can be used for the
preparation of medicaments.

[0002] The present invention relates to compounds and to the use of
compounds for the treatment of diseases which are accompanied by an
increase in the lysophosphatidic acid level, furthermore to
pharmaceutical compositions which comprise these compounds.

[0003] In detail, the present invention relates to compounds of the
formula I, which preferably inhibit one or more enzymes which regulate
and/or modulate the lysophosphatidic acid (or LPA for short) level, to
compositions which comprise these compounds, and to processes for the use
thereof for the treatment of diseases and complaints, such as
angiogenesis, cancer, tumour formation, growth and propagation,
arteriosclerosis, ocular diseases, choroidal neovascularisation and
diabetic retinopathy, inflammatory diseases, arthritis,
neurodegeneration, restenosis, wound healing or transplant rejection. In
particular, the compounds according to the invention are suitable for the
therapy or prophylaxis of cancer diseases.

[0005] For this reason, it is desirable to lower the LPA level for the
treatment of tumour patients. This can be achieved by the inhibition of
enzymes which are involved in LPA biosynthesis, such as, for example,
autotaxin (ATX, Sano et al. 2002, J. Biol. Chem. Vol. 277, page 21197 and
Aoki et al. 2003, J. Biol. Chem. Vol. 277 page 48737). Autotaxin belongs
to the enzyme family of the nucleotides pyrophosphatases and
phosphodiesterases (Goding et al. 1998, Immunol. Rev. Vol. 161, page 11)
and represents an important starting point in antitumour therapy (Mills
et al. 2003 Nat. Rev. Cancer Vol. 3, page 582 and Goto et al. 2004 J.
Cell. Biochem. Vol. 92, page 1115) since it is expressed to an increased
extent in tumours and causes tumour cell proliferation and invasion into
neighbouring tissue, which can result in metastases formation (Nam et al.
2000, Oncogene, Vol. 19 page 241). In addition, autotaxin together with
other angiogenetic factors causes blood vessel formation in the course of
angiogenesis (Nam et al. 2001, Cancer Res. Vol. 61 page. 6938).
Angiogenesis is an important process in tumour growth, which ensures
supply of the tumour with nutrients.

[0006] For this reason, inhibition of angiogenesis is an important
starting point in cancer and tumour therapy, with which the tumour can be
starved to a certain extent (Folkman, 2007, Nature Reviews Drug Discovery
Vol. 6, page 273-286).

[0007] Surprisingly, it has been found that the compounds according to the
invention cause specific inhibition of the enzyme family of the
nucleotides pyrophosphatases and phosphodiesterases, in particular
autotaxin. The compounds according to the invention preferably exhibit an
advantageous biological activity, which can easily be detected in the
test described, for example, herein. In tests of this type, the compounds
according to the invention preferably exhibit and cause an inhibiting
effect, which is usually documented by 1050 values in a suitable range,
preferably in the micromolar range and more preferably in the nanomolar
range.

[0008] In general, all solid and non-solid tumours can be treated with the
compounds of the formula I, such as, for example, monocytic leukaemia,
brain, urogenital, lymphatic system, stomach, laryngeal, ovarian and lung
carcinoma, including lung adenocarcinoma and small-cell lung carcinoma.
Further examples include prostate, pancreatic and breast carcinoma.

[0009] As discussed herein, effects of the compound according to the
invention are relevant for various diseases. Accordingly, the compounds
according to the invention are useful in the prophylaxis and/or treatment
of diseases which are influenced by inhibition of one or more nucleotides
pyrophosphatases and/or phosphodiesterases, in particular autotaxin.

[0010] The present invention therefore relates to compounds according to
the invention as medicaments and/or medicament active ingredients in the
treatment and/or prophylaxis of the said diseases and to the use of
compounds according to the invention for the preparation of a
pharmaceutical agent for the treatment and/or prophylaxis of the said
diseases, and also to a method for the treatment of the said diseases
comprising the administration of one or more compounds according to the
invention to a patient in need of such administration.

[0011] It can be shown that the compounds according to the invention have
an advantageous action in a xenotransplant tumour model.

[0012] The host or patient can belong to any mammalian species, for
example a primate species, in particular humans; rodents, including mice,
rats and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal
models are of interest for experimental investigations, where they
provide a model for the treatment of a human disease.

[0013] The sensitivity of a certain cell to treatment with the compounds
according to the invention can be determined by testing in vitro.
Typically, a culture of the cell is combined with a compound according to
the invention at various concentrations for a time which is sufficient to
enable the active agents to induce cell death or to inhibit cell
migration or to block the cellular secretion of angiogenesis-promoting
substances, usually between approximately one hour and one week. For
testing in vitro, cultivated cells from a biopsy sample can be used. The
viable cells remaining after the treatment are then counted.

[0014] The dose varies depending on the specific compound used, the
specific disease, the patient status, etc. Typically, a therapeutic dose
is sufficient to considerably reduce the undesired cell population in the
target tissue, while the viability of the patient is maintained. The
treatment is generally continued until a considerable reduction has
occurred, for example at least about a 50% reduction in the cell burden,
and can be continued until essentially no undesired cells can be detected
in the body.

PRIOR ART

[0015] Compounds which are capable of inhibiting autotaxin are described
in Peng et al. Bioorganic & Medicinal Chemistry Letters (17, 2007, page
1634-1640). The compounds described therein are lipid analogues, which do
not have any structural features in common with the compounds according
to the invention.

[0037] Compounds of the formula I also mean pharmaceutically usable
derivatives thereof, optically active forms (stereoisomers), tautomers,
polymorphs, enantiomers, racemates, diastereomers and the hydrates and
solvates of these compounds. The term solvates of the compounds is taken
to mean adductions of inert solvent molecules onto the compounds which
form owing to their mutual attractive force. solvates are, for example,
mono- or dihydrates or alcoholates.

[0038] Pharmaceutically usable derivatives are taken to mean, for example,
the salts of the compounds according to the invention and also so-called
prodrug compounds.

[0039] Prodrug derivatives are taken to mean compounds of the formula I
which have been modified by means of, for example, alkyl or acyl groups,
sugars or oligopeptides and which are rapidly cleaved in the organism to
form the effective compounds according to the invention.

[0040] These also include biodegradable polymer derivatives of the
compounds according to the invention, as described, for example, in Int.
J. Pharm. 115, 61-67 (1995).

[0041] The expression "effective amount" denotes the amount of a
medicament or of a pharmaceutical active ingredient which causes in a
tissue, system, animal or human biological or medical response which is
sought or desired, for example, by a researcher or physician.

[0042] In addition, the expression "therapeutically effective amount"
denotes an amount which, compared with a corresponding subject who has
not received this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,
syndrome, condition, complaint, disorder or side effects or also the
reduction in the advance of a disease, complaint or disorder.

[0043] The expression "therapeutically effective amount" also encompasses
the amounts which are effective for increasing normal physiological
function.

[0044] The invention also relates to the use of mixtures of the compounds
of the formula I, for example mixtures of two diastereomers, for example
in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

[0045] These are particularly preferably mixtures of stereoisomeric
compounds.

[0046] The invention relates to the compounds of the formula I and salts
thereof and to a process for the preparation of compounds of the formula
I according to the patent claims and pharmaceutically usable salts, and
stereoisomers thereof, characterised in that [0047] for the preparation
of compounds of the formula I, [0048] a compound of the formula II

[0048] ##STR00002## [0049] in which R2, R3, R4,
R5 and p, have the meanings indicated in claim 1, is reacted with a
compound of the formula III or IV

[0049] ##STR00003## [0050] in which [0051] R1, m, D, Z, X and Y
have the meanings indicated in claim 1 and L is a halogen, tosylate,
mesylate or triflate, and/or a base or acid of the formula I is converted
into one of its salts.

[0069] Throughout the invention, all radicals which occur more than once,
such as, for example, R, may be identical or different, i.e. are
independent of one another.

[0070] The compounds of the formula I may have one or more chiral centres
and can therefore occur in various stereoisomeric forms. The formula I
encompasses all these forms.

[0071] Accordingly, the invention relates, in particular, to the compounds
of the formula I in which at least one of the said radicals has one of
the preferred meanings indicated above.

[0072] Some preferred groups of compounds may be expressed by the
following sub-formulae Ia to Ie, which conform to the formula I and in
which the radicals not designated in greater detail have the meaning
indicated for the formula I, but in which [0073] in Ia R1 denotes H,
Hal, CN, phenyl, OA or OH; [0074] in Ib R4 denotes H, Hal, A or OH;
[0075] in Ic R5H; [0076] in Id R2, R3 together denotes
morpholinyl, piperazinyl, 1-methylpiperazinyl,
1-ethyl-4-methylpiperazinyl, 2-(4-methylpiperazin-1-yl)-ethyl,
1-methyl-4-propylpiperazinyl, 1-cyclopentyl-4-methylpiperazinyl,
1-benzyl-4-methyl-1,4-diazepanyl or 1-benzyl-4-methylpiperazinyl; [0077]
in Ie Het1 particularly preferably denotes piperazyl, morpholinyl,
pperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
pyrimidinyl, triazolyl, benzotriazylyl, benzofuranyl,
2,3-dihydrobenzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl,
each of which is unsubstituted or mono-, di- or trisubstituted by A
and/or (CH2)nAr. [0078] In If Het2 particularly preferably
denotes pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, each of
which is unsubstituted or mono- or disubstituted by Hal, OH, OA, A and/or
═O. [0079] in Ig R1 denotes H, Hal, CN, phenyl, OA or OH;
[0080] R4 denotes H, Hal, A or OH; [0081] R5 denotes H and
[0082] R2, R3 together denote morpholinyl, piperazinyl,
1-methylpiperazinyl, 1-ethyl-4-methylpiperazinyl,
2-(4-methylpiperazin-1-yl)-ethyl, 1-methyl-4-propylpiperazinyl,
1-cyclopentyl-4-methylpiperazinyl, 1-benzyl-4-methyl-1,4-diazepanyl or
1-benzyl-4-methylpiperazinyl, [0083] Het1 particularly preferably
denotes piperazyl, morpholinyl, pperidinyl, pyrrolidinyl, furanyl,
thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, benzotriazylyl,
benzofuranyl, 2,3-dihydrobenzoxazolyl, benzoxazolyl, dihydrobenzofuranyl
or tetrazolyl, each of which is unsubstituted or mono-, di- or
trisubstituted by A and/or (CH2)nAr, [0084] Het2
particularly preferably denotes pyrrolidinyl, morpholinyl, piperidinyl or
piperazinyl, each of which is unsubstituted or mono- or di substituted by
Hal, OH, OA, A and/or ═O, and pharmaceutically usable salts and
stereoisomers thereof, including mixtures thereof in all ratios.

[0085] The compounds of the formula I and also the starting materials for
their preparation are, in addition, prepared by methods known per se, as
described in the literature (for example in the standard works, such as
Houben-Weyl, Methoden der organischen Chemie [Methods of Organic
Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction
conditions which are known and suitable for the said reactions. Use can
also be made here of variants known per se which are not mentioned here
in greater detail.

[0086] The starting materials can, if desired, also be formed in situ by
not isolating them from the reaction mixture, but instead immediately
converting them further into the compounds of the formula I.

[0087] Compounds of the formula I can preferably be obtained by reacting a
compound of the formula II with a compound of the formula III.

[0088] Depending on the conditions used, the reaction time is between a
few minutes and 14 days, the reaction temperature is between about
-30° and 140°, normally between -10° and 90°,
in particular between about 0° and about 70°.

[0089] Examples of suitable inert solvents are hydrocarbons, such as
hexane, petroleum ether, benzene, toluene or xylene; chlorinated
hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon
tetrachloride, chloroform or dichloromethane; alcohols, such as methanol,
ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such
as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;
glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,
ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or
butanone; amides, such as acetamide, dimethylacetamide or
dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such
as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as
formic acid or acetic acid; nitro compounds, such as nitromethane or
nitrobenzene; esters, such as ethyl acetate, or mixtures of the said
solvents.

[0091] The starting compounds of the formulae II, II and IV are generally
known. If they are novel, however, they can be prepared by methods known
per se. The starting materials are generally also commercially available.

[0092] The said compounds according to the invention can be used in their
final non-salt form. On the other hand, the present invention also
encompasses the use of these compounds in the form of their
pharmaceutically acceptable salts, which can be derived from various
organic and inorganic acids and bases by procedures known in the art.
Pharmaceutically acceptable salt forms of the compounds of the formula I
are for the most part prepared by conventional methods. If the compound
of the formula I contains a carboxyl group, one of its suitable salts can
be formed by reacting the compound with a suitable base to give the
corresponding base-addition salt. Such bases are, for example, alkali
metal hydroxides, including potassium hydroxide, sodium hydroxide and
lithium hydroxide; alkaline-earth metal hydroxides, such as barium
hydroxide and calcium hydroxide; alkali metal alkoxides, for example
potassium ethoxide and sodium propoxide; and various organic bases, such
as piperidine, diethanolamine and N-methylglutamine. The aluminium salts
of the compounds of the formula I are likewise included. In the case of
certain compounds of the formula I, acid-addition salts can be formed by
treating these compounds with pharmaceutically acceptable organic and
inorganic acids, for example hydrogen halides, such as hydrogen chloride,
hydrogen bromide or hydrogen iodide, other mineral acids and
corresponding salts thereof, such as sulfate, nitrate or phosphate and
the like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,
toluenesulfonate and benzenesulfonate, and other organic acids and
corresponding salts thereof, such as acetate, trifluoroacetate, tartrate,
maleate, succinate, citrate, benzoate, salicylate, ascorbate and the
like. Accordingly, pharmaceutically acceptable acid-addition salts of the
compounds of the formula I include the following: acetate, adipate,
alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate),
bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate,
caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate,
digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,
ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate,
glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,
hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,
isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate,
metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate,
2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,
pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,
phosphonate, phthalate, but this does not represent a restriction.

[0093] Furthermore, the base salts of the compounds according to the
invention include aluminium, ammonium, calcium, copper, iron(III),
iron(II), lithium, magnesium, manganese(III), manganese(II), potassium,
sodium and zinc salts, but this is not intended to represent a
restriction. Of the above-mentioned salts, preference is given to
ammonium; the alkali metal salts sodium and potassium, and the
alkaline-earth metal salts calcium and magnesium. Salts of the compounds
of the formula I which are derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary and tertiary
amines, substituted amines, also including naturally occurring
substituted amines, cyclic amines, and basic ion exchanger resins, for
example arginine, betaine, caffeine, chloroprocaine, choline,
N,N'-dibenzylethylenediamine(benzathine), dicyclohexylamine,
diethanolamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine, purines,
theobromine, triethanolamine, triethylamine, trimethylamine,
tripropylamine and tris(hydroxymethyl)-methylamine (tromethamine), but
this is not intended to represent a restriction.

[0094] Compounds of the present invention which contain basic
nitrogen-containing groups can be quaternised using agents such as
(C1-C4)alkyl halides, for example methyl, ethyl, isopropyl and
tert-butyl chloride, bromide and iodide; di(C1-C4)alkyl
sulfates, for example dimethyl, diethyl and diamyl sulfate;
(C10-C18)alkyl halides, for example decyl, dodecyl, lauryl,
myristyl and stearyl chloride, bromide and iodide; and
aryl(C1-C4)alkyl halides, for example benzyl chloride and
phenethyl bromide. Both water- and oil-soluble compounds according to the
invention can be prepared using such salts.

[0096] The acid-addition salts of basic compounds of the formula I are
prepared by bringing the free base form into contact with a sufficient
amount of the desired acid, causing the formation of the salt in a
conventional manner. The free base can be regenerated by bringing the
salt form into contact with a base and isolating the free base in a
conventional manner. The free base forms differ in a certain respect from
the corresponding salt forms thereof with respect to certain physical
properties, such as solubility in polar solvents; for the purposes of the
invention, however, the salts otherwise correspond to the respective free
base forms thereof.

[0097] As mentioned, the pharmaceutically acceptable base-addition salts
of the compounds of the formula I are formed with metals or amines, such
as alkali metals and alkaline-earth metals or organic amines. Preferred
metals are sodium, potassium, magnesium and calcium. Preferred organic
amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

[0098] The base-addition salts of acidic compounds according to the
invention are prepared by bringing the free acid form into contact with a
sufficient amount of the desired base, causing the formation of the salt
in a conventional manner. The free acid can be regenerated by bringing
the salt form into contact with an acid and isolating the free acid in a
conventional manner. The free acid forms differ in a certain respect from
the corresponding salt forms thereof with respect to certain physical
properties, such as solubility in polar solvents; for the purposes of the
invention, however, the salts otherwise correspond to the respective free
acid forms thereof.

[0099] If a compound according to the invention contains more than one
group which is capable of forming pharmaceutically acceptable salts of
this type, the invention also encompasses multiple salts. Typical
multiple salt forms include, for example, bitartrate, diacetate,
difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but
this is not intended to represent a restriction.

[0100] With regard to that stated above, it can be seen that the
expression "pharmaceutically acceptable salt" in the present connection
is taken to mean an active ingredient which comprises a compound of the
formula I in the form of one of its salts, in particular if this salt
form imparts improved pharmacokinetic properties on the active ingredient
compared with the free form of the active ingredient or any other salt
form of the active ingredient used earlier. The pharmaceutically
acceptable salt form of the active ingredient can also provide this
active ingredient for the first time with a desired pharmacokinetic
property which it did not have earlier and can even have a positive
influence on the pharmacodynamics of this active ingredient with respect
to its therapeutic efficacy in the body.

[0101] The invention furthermore relates to medicaments comprising at
least one compound of the formula I and/or pharmaceutically usable salts
and stereoisomers thereof, including mixtures thereof in all ratios, and
optionally excipients and/or adjuvants.

[0102] Pharmaceutical formulations can be administered in the form of
dosage units which comprise a predetermined amount of active ingredient
per dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,
preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a
compound according to the invention, depending on the condition treated,
the method of administration and the age, weight and condition of the
patient, or pharmaceutical formulations can be administered in the form
of dosage units which comprise a predetermined amount of active
ingredient per dosage unit. Preferred dosage unit formulations are those
which comprise a daily dose or part-dose, as indicated above, or a
corresponding fraction thereof of an active ingredient. Furthermore,
pharmaceutical formulations of this type can be prepared using a process
which is generally known in the pharmaceutical art.

[0103] Pharmaceutical formulations can be adapted for administration via
any desired suitable method, for example by oral (including buccal or
sublingual), rectal, nasal, topical (including buccal, sublingual or
transdermal), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous or intradermal) methods. Such formulations can
be prepared using all processes known in the pharmaceutical art by, for
example, combining the active ingredient with the excipient(s) or
adjuvant(s).

[0104] Pharmaceutical formulations adapted for oral administration can be
administered as separate units, such as, for example, capsules or
tablets; powders or granules; solutions or suspensions in aqueous or
non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid
emulsions or water-in-oil liquid emulsions.

[0105] Thus, for example, in the case of oral administration in the form
of a tablet or capsule, the active-ingredient component can be combined
with an oral, non-toxic and pharmaceutically acceptable inert excipient,
such as, for example, ethanol, glycerol, water and the like. Powders are
prepared by comminuting the compound to a suitable fine size and mixing
it with a pharmaceutical excipient comminuted in a similar manner, such
as, for example, an edible carbohydrate, such as, for example, starch or
mannitol. A flavour, preservative, dispersant and dye may likewise be
present.

[0106] Capsules are produced by preparing a powder mixture as described
above and filling shaped gelatine shells therewith. Glidants and
lubricants, such as, for example, highly disperse silicic acid, talc,
magnesium stearate, calcium stearate or polyethylene glycol in solid
form, can be added to the powder mixture before the filling operation. A
disintegrant or solubiliser, such as, for example, agar-agar, calcium
carbonate or sodium carbonate, may likewise be added in order to improve
the availability of the medicament after the capsule has been taken.

[0107] In addition, if desired or necessary, suitable binders, lubricants
and disintegrants as well as dyes can likewise be incorporated into the
mixture. Suitable binders include starch, gelatine, natural sugars, such
as, for example, glucose or beta-lactose, sweeteners made from maize,
natural and synthetic rubber, such as, for example, acacia, tragacanth or
sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and
the like. The lubricants used in these dosage forms include sodium
oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. The disintegrants include, without
being restricted thereto, starch, methylcellulose, agar, bentonite,
xanthan gum and the like. The tablets are formulated by, for example,
preparing a powder mixture, granulating or dry-pressing the mixture,
adding a lubricant and a disintegrant and pressing the entire mixture to
give tablets. A powder mixture is prepared by mixing the compound
comminuted in a suitable manner with a diluent or a base, as described
above, and optionally with a binder, such as, for example,
carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a
dissolution retardant, such as, for example, paraffin, an absorption
accelerator, such as, for example, a quaternary salt, and/or an
absorbant, such as, for example, bentonite, kaolin or dicalcium
phosphate. The powder mixture can be granulated by wetting it with a
binder, such as, for example, syrup, starch paste, acadia mucilage or
solutions of cellulose or polymer materials and pressing it through a
sieve. As an alternative to granulation, the powder mixture can be run
through a tabletting machine, giving lumps of non-uniform shape, which
are broken up to form granules. The granules can be lubricated by
addition of stearic acid, a stearate salt, talc or mineral oil in order
to prevent sticking to the tablet casting moulds. The lubricated mixture
is then pressed to give tablets. The compounds according to the invention
can also be combined with a free-flowing inert excipient and then pressed
directly to give tablets without carrying out the granulation or
drypressing steps. A transparent or opaque protective layer consisting of
a shellac sealing layer, a layer of sugar or polymer material and a gloss
layer of wax may be present. Dyes can be added to these coatings in order
to be able to differentiate between different dosage units.

[0108] Oral liquids, such as, for example, solution, syrups and elixirs,
can be prepared in the form of dosage units so that a given quantity
comprises a prespecified amount of the compound. Syrups can be prepared
by dissolving the compound in an aqueous solution with a suitable
flavour, while elixirs are prepared using a non-toxic alcoholic vehicle.
Suspensions can be formulated by dispersion of the compound in a
non-toxic vehicle. Solubilisers and emulsifiers, such as, for example,
ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,
preservatives, flavour additives, such as, for example, peppermint oil or
natural sweeteners or saccharin, or other artificial sweeteners and the
like, can likewise be added.

[0109] The dosage unit formulations for oral administration can, if
desired, be encapsulated in microcapsules. The formulation can also be
prepared in such a way that the release is extended or retarded, such as,
for example, by coating or embedding of particulate material in polymers,
wax and the like.

[0110] The compounds of the formula I and salts, solvates and
physiologically functional derivatives thereof can also be administered
in the form of liposome delivery systems, such as, for example, small
unilamellar vesicles, large unilamellar vesicles and multilamellar
vesicles. Liposomes can be formed from various phospholipids, such as,
for example, cholesterol, stearylamine or phosphatidylcholines.

[0111] The compounds of the formula I and the salts, solvates and
physiologically functional derivatives thereof can also be delivered
using monoclonal anti-bodies as individual carriers to which the compound
molecules are coupled.

[0112] The compounds can also be coupled to soluble polymers as targeted
medicament carriers. Such polymers may encompass polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamidophenol,
polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,
substituted by palmitoyl radicals. The compounds may furthermore be
coupled to a class of biodegradable polymers which are suitable for
achieving controlled release of a medicament, for example polylactic
acid, poly-epsilon-caprolactone, polyhydroxybutyric acid,
polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and
crosslinked or amphipathic block copolymers of hydrogels.

[0113] Pharmaceutical formulations adapted for transdermal administration
can be administered as independent plasters for extended, close contact
with the epidermis of the recipient. Thus, for example, the active
ingredient can be delivered from the plaster by iontophoresis, as
described in general terms in Pharmaceutical Research, 3(6), 318 (1986).

[0115] For the treatment of the eye or other external tissue, for example
mouth and skin, the formulations are preferably applied as topical
ointment or cream. In the case of formulation to give an ointment, the
active ingredient can be employed either with a paraffinic or a
water-miscible cream base. Alternatively, the active ingredient can be
formulated to give a cream with an oil-in-water cream base or a
water-in-oil base.

[0116] Pharmaceutical formulations adapted for topical application to the
eye include eye drops, in which the active ingredient is dissolved or
suspended in a suitable carrier, in particular an aqueous solvent.

[0118] Pharmaceutical formulations adapted for rectal administration can
be administered in the form of suppositories or enemas.

[0119] Pharmaceutical formulations adapted for nasal administration in
which the carrier substance is a solid comprise a coarse powder having a
particle size, for example, in the range 20-500 microns, which is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation via the nasal passages from a container containing the powder
held close to the nose. Suitable formulations for administration as nasal
spray or nose drops with a liquid as carrier substance encompass
active-ingredient solutions in water or oil.

[0120] Pharmaceutical formulations adapted for administration by
inhalation encompass finely particulate dusts or mists, which can be
generated by various types of pressurised dispensers with aerosols,
nebulisers or insufflators.

[0122] Pharmaceutical formulations adapted for parenteral administration
include aqueous and non-aqueous sterile injection solutions comprising
antioxidants, buffers, bacteriostatics and solutes, by means of which the
formulation is rendered isotonic with the blood of the recipient to be
treated; and aqueous and non-aqueous sterile suspensions, which may
comprise suspension media and thickeners. The formulations can be
administered in single-dose or multidose containers, for example sealed
ampoules and vials, and stored in freeze-dried (lyophilised) state, so
that only the addition of the sterile carrier liquid, for example water
for injection purposes, immediately before use is necessary. Injection
solutions and suspensions prepared in accordance with the recipe can be
prepared from sterile powders, granules and tablets.

[0123] It goes without saying that, in addition to the above particularly
mentioned constituents, the formulations may also comprise other agents
usual in the art with respect to the particular type of formulation;
thus, for example, formulations which are suitable for oral
administration may comprise flavours.

[0124] A therapeutically effective amount of a compound of the formula I
depends on a number of factors, including, for example, the age and
weight of the animal, the precise condition that requires treatment, and
its severity, the nature of the formulation and the method of
administration, and is ultimately determined by the treating doctor or
vet. However, an effective amount of a compound according to the
invention for the treatment of neoplastic growth, for example colon or
breast carcinoma, is generally in the range from 0.1 to 100 mg/kg of body
weight of the recipient (mammal) per day and particularly typically in
the range from 1 to 10 mg/kg of body weight per day. Thus, the actual
amount per day for an adult mammal weighing 70 kg is usually between 70
and 700 mg, where this amount can be administered as a single dose per
day or more usually in a series of part-doses (such as, for example, two,
three, four, five or six) per day, so that the total daily dose is the
same. An effective amount of a salt or solvate or of a physiologically
functional derivative thereof can be determined as the fraction of the
effective amount of the compound according to the invention per se. It
can be assumed that similar doses are suitable for the treatment of other
conditions mentioned above.

[0125] The invention furthermore relates to medicaments comprising at
least one compound of the formula I and/or pharmaceutically usable
derivatives, solvates and stereoisomers thereof, including mixtures
thereof in all ratios, and at least one further medicament active
ingredient.

[0126] The invention also relates to a set (kit) consisting of separate
packs of [0127] (a) an effective amount of a compound of the formula I
and/or pharmaceutically usable derivatives, solvates and stereoisomers
thereof, including mixtures thereof in all ratios, and [0128] (b) an
effective amount of a further medicament active ingredient.

[0129] The set comprises suitable containers, such as boxes, individual
bottles, bags or ampoules. The set may, for example, comprise separate
ampoules, each containing an effective amount of a compound of the
formula I and/or pharmaceutically usable derivatives, solvates and
stereoisomers thereof, including mixtures thereof in all ratios, and an
effective amount of a further medicament active ingredient in dissolved
or lyophilised form.

[0130] The medicaments from Table 1 are preferably, but not exclusively,
combined with the compounds of the formula I. A combination of the
formula I and medicaments from Table I can also be combined with
compounds of the formula VI.

[0131] The compounds of the formula I are preferably combined with the
with known anti-cancer agents:

[0132] These known anti-cancer agents include the following: oestrogen
receptor modulators, androgen receptor modulators, retinoid receptor
modulators, cytotoxic agents, antiproliferative agents, prenyl-protein
transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease
inhibitors, reverse transcriptase inhibitors and other angiogenesis
inhibitors. The present compounds are particularly suitable for
administration at the same time as radiotherapy. The synergistic effects
of inhibition of VEGF in combination with radiotherapy have been
described in the art (see WO 00/61186). "Oestrogen receptor modulators"
refers to compounds which interfere with or inhibit the binding of
oestrogen to the receptor, regardless of mechanism. Examples of oestrogen
receptor modulators include, but are not limited to, tamoxifen,
raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant,
4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]ph-
enyl]-2H-1-benzopyran-3-yl]phenyl 2,2-dimethylpropanoate,
4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.
"Androgen receptor modulators" refers to compounds which interfere with
or inhibit the binding of androgens to the receptor, regardless of
mechanism. Examples of androgen receptor modulators include finasteride
and other 5α-reductase inhibitors, nilutamide, flutamide,
bicalutamide, liarozole and abiraterone acetate.

[0133] "Retinoid receptor modulators" refers to compounds which interfere
with or inhibit the binding of retinoids to the receptor, regardless of
mechanism. Examples of such retinoid receptor modulators include
bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,
α-difluoromethylornithine, ILX23-7553,
trans-N-(4'-hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.

[0134] "Cytotoxic agents" refers to compounds which result in cell death
primarily through direct action on the cellular function or inhibit or
interfere with cell myosis, including alkylating agents, tumour necrosis
factors, intercalators, microtubulin inhibitors and topoisomerase
inhibitors.

[0139] Particular preference is given to the use of the compound according
to the invention for the treatment and prophylaxis of tumour diseases.

[0140] The tumour is preferably selected from the group of tumours of the
squamous epithelium, of the bladder, of the stomach, of the kidneys, of
head and neck, of the oesophagus, of the cervix, of the thyroid, of the
intestine, of the liver, of the brain, of the prostate, of the urogenital
tract, of the lymphatic system, of the stomach, of the larynx and/or of
the lung.

[0142] Preference is furthermore given to the use for the treatment of a
tumour of the blood and immune system, preferably for the treatment of a
tumour selected from the group of acute myeloid leukaemia, chronic
myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic
leukaemia.

[0143] In another aspect, the invention encompasses a for the treatment of
a patient who has a neoplasm, such as a cancer, by administration of a
compound of the formula (I) in combination with an antiproliferative
agent. Suitable antiproliferative agents encompass those provided in
Table 1.

[0144] Above and below, all temperatures are indicated in ° C. In
the following examples, "conventional work-up" means: if necessary, water
is added, the pH is adjusted, if necessary, to values between 2 and 10,
depending on the constitution of the end product, the mixture is
extracted with ethyl acetate or dichloromethane, the phases are
separated, the organic phase is dried over sodium sulfate and evaporated,
and the product is purified by chromatography on silica gel and/or by
crystallisation. Rt values are determined by HPLC using eluents
mentioned. [0145] Mass spectrometry (MS): EI (electron impact ionisation)
M.sup.+ [0146] FAB (fast atom bombardment) (M+H).sup.+ [0147] ESI
(electrospray ionisation) (M+H).sup.+ [0148] APCI-MS (atmospheric
pressure chemical ionisation--mass spectrometry) (M+H).sup.+

[0165] a. 0.48 g (1.5 mmol) of 1 and 0.70 g (1.5 mmol) of PyBroP are
dissolved in 20 ml of DMF and stirred for 5 min. 1.67 ml (1.5 mmol) of
methylpiperazine are then added, and the mixture is stirred at room
temperature (RT) for 2 hours. The solvent is removed in a rotary
evaporator, diluted with water (100 ml) and extracted 2× with EA.
The organic phase is dried over magnesium sulfate, filtered off and
evaporated to dryness. Purification by means of preparative HPLC gives
0.29 g (48.3%) of 2 as colourless amorphous product.

[0166] b. 0.26 g (0.65 mmol) of 2 are dissolved in 5 ml of THF, 2 ml of
methanol and 0.3 ml of acetic acid (100%), 0.3 g of 5% Pd/C is added, and
the mixture is hydrogenated at RT for 32 h. The catalyst is then filtered
off, and the solvent is evaporated in vacuo. The residue is purified by
means of preparative HPLC, giving 76 mg (37.7%) of starting material 3 as
amorphous product.

[0167] c. 0.79 g (5 mmol) of 5-chloro-2-methoxyphenylamine are dissolved
in 50 ml of DCM. 0.7 ml (5 mmol) of triethylamine are added. 0.42 ml (5
mmol) of bromoacetyl chloride is then added dropwise with ice-cooling.
The mixture is then stirred at RT for 2 h. The mixture is washed with
water. The organic phase is then dried over sodium sulfate, filtered off,
and the solvent is evaporated in vacuo. The starting material (4, 1.2 g,
86%) is reacted further without purification.

[0168] d. 72 mg (0.23 mmol) of 3, 65 mg (0.23 mmol) of 4 and 76 mg (0.23
mmol) of caesium carbonate are stirred in 5 ml of DMF for 18 hours. Water
is then added to the batch, which is then extracted with glacial acetic
acid. The organic phase is dried over magnesium sulfate, filtered off and
evaporated to dryness. The residue is purified by means of preparative
HPLC, giving 54 mg (46%) of substance "A1" as amorphous product.

[0255] 0.17 g (0.5 mmol) of 3 (synthesis is described in Example 1), 0.11
g (0.5 mmol) of 2,4-dichlorophenylpropionic acid, 96 mg (0.5 mmol) of
N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 68 mg (0.5
mmol) of HOBt and 0.07 ml (0.5 mmol) of triethylamine are dissolved in 5
ml of DMF and stirred at RT for 20 h. The solvent is then evaporated in a
rotary evaporator. The residue is taken up in aqueous Na2CO3
solution and EA and extracted by shaking. The organic phase is separated
off and dried over magnesium sulfate, filtered off and evaporated to
dryness. The residue is dissolved in 1n HCl and freeze-dried, giving 0.18
g (66%) of 6 as colourless amorphous product.

[0256] The following compounds are prepared analogously to Example 3 using
the corresponding precursor (9):

[0356] The autotaxin activity is measured indirectly using Amplex Red
reagent. Amplex Red is measured here as fluorogenic indicator for the
H2O2 formed. In detail, autotaxin converts the substrate
lysophosphatidylcholine (LPC) into phosphocholine and lysophosphatidylic
acid (LPA). After this reaction, the phosphocholine is reacted with
alkaline phosphatase to give inorganic phosphate and choline. In the next
step, choline is oxidised by choline oxidase to give betaine, with
formation of H2O2. H2O2 reacts with Amplex Red
reagent in the presence of peroxidase (horseradish peroxidase) in a 1:1
stoichiometry and forms the highly fluorescent resorufin. The
fluorescence is measured in a reaction-dependent kinetic mode in order
that fluorescent signals from possible other fluorescent substances which
are not involved in the reaction can be corrected out.

Test Procedure

[0357] 1.5 μl of a standard solution or of the test substances
(substances with the name A(n))in individual concentrations dissolved in
20 mM Hepes pH 7.2 with a maximum of 7.7% of DMSO are pre-incubated
together with 10 μl (16 ng) of highly purified recombinant autotaxin
in a black microtitre plate provided with 384 wells at 22° C. for
30 min. The reaction is then initiated by addition of 5 μl of
L-α-lysophosphatidylcholine (LPC), where the final concentration of
LPC is 75 μM. The mixture is incubated at 37° C. for 90 min.
After the incubation, Amplex Red reagent, peroxidase (horseradish
peroxidase) and choline oxidase is added, and the fluorescence is
immediately measured at 612 nm with excitation of 485 nm in a "Tecan
Ultra multimode" reader. The activity of autotaxin is calculated
indirectly via detection of the H2O2 formed.

[0366] A solution of 100 g of an active ingredient of the formula I and 5
g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted
to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into
injection vials, lyophilised under sterile conditions and sealed under
sterile conditions. Each injection vial contains 5 mg of active
ingredient.

EXAMPLE C

Suppositories

[0367] A mixture of 20 g of an active ingredient of the formula I with 100
g of soya lecithin and 1400 g of cocoa butter is melted, poured into
moulds and allowed to cool. Each suppository contains 20 mg of active
ingredient.

EXAMPLE D

Solution

[0368] A solution is prepared from 1 g of an active ingredient of the
formula I, 9.38 g of NaH2PO4.2H2O, 28.48 g of
Na2HPO4.12H2O and 0.1 g of benzalkonium chloride in 940 ml
of bidistilled water. The pH is adjusted to 6.8, and the solution is made
up to 1 l and sterilised by irradiation. This solution can be used in the
form of eye drops.

EXAMPLE E

Ointment

[0369] 500 mg of an active ingredient of the formula I are mixed with 99.5
g of Vaseline under aseptic conditions.

EXAMPLE F

Tablets

[0370] A mixture of 1 kg of active ingredient of the formula I, 4 kg of
lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium
stearate is pressed in a conventional manner to give tablets in such a
way that each tablet contains 10 mg of active ingredient.

EXAMPLE G

Dragees

[0371] Tablets are pressed analogously to Example E and subsequently
coated in a conventional manner with a coating of sucrose, potato starch,
talc, tragacanth and dye.

EXAMPLE H

Capsules

[0372] 2 kg of active ingredient of the formula I are introduced into hard
gelatine capsules in a conventional manner in such a way that each
capsule contains 20 mg of the active ingredient.

EXAMPLE I

Ampoules

[0373] A solution of 1 kg of active ingredient of the formula I in 60 l of
bidistilled water is sterile filtered, transferred into ampoules,
lyophilised under sterile conditions and sealed under sterile conditions.
Each ampoule contains 10 mg of active ingredient.